Molecular Analysis of p53, MDM2, and H-ras Genes in Osteosarcoma and Malignant Fibrous Histiocytoma of Bone in Patients Older than 40 Years

Kawaguchi, Ken Ichi; Oda, Yoshinao; Sakamoto, Akio; Saito, Tsuyoshi; Tamiya, Sadafumi; Iwamoto, Yukihide; Tsuneyoshi, Masazumi

doi:10.1097/01.mp.0000024264.48690.ea

Cited by 43 publications

(31 citation statements)

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“…Only one amplification (2.8%) was observed for MDM2 (cases 19). This is significantly lower than the values of 20-30% generally found in sporadic sarcomas (Miller et al, 1996;Kawaguchi et al, 2002;Perucca-Lostanlen et al, 2004), and strengthens the conclusion regarding the secondary role played by the ARF/MDM2/MDMX pathway in the radiation-induced sarcomas.…”

Section: Ink4acontrasting

confidence: 42%

RB1 and TP53 pathways in radiation-induced sarcomas

et al. 2007

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The tumour suppressor genes, TP53 and RB1, and four genes involved in their regulation, INK4a, ARF, MDM2 and MDMX, were analysed in a series of 36 postradiotherapy radiation-induced sarcomas. One-third of the tumours developed in patients carrying a germline mutation of RB1 that predisposed them to retinoblastoma and radiation-induced sarcomas. The genetic inactivation of RB1 and/or TP53 genes was frequently observed in these sarcomas. These inactivations were owing to an interplay between point mutations and losses of large chromosome segments. Radiation-induced somatic mutations were observed in TP53, but not in RB1 or in the four other genes, indicating an early role of TP53 in the radio-sarcomagenesis. RB1 and TP53 genes were biallelically coinactivated in all sarcomas developing in the context of the predisposition, indicating that both genes played a major role in the formation of these sarcomas. In the absence of predisposition, TP53 was biallelically inactivated in one-third of the sarcomas, whereas at least one allele of RB1 was wild type. In both genetic contexts, the TP53 pathway was inactivated by genetic lesions and not by the activation of the ARF/MDM2/MDMX pathway, as recently shown in retinoblastomas. Together, these findings highlight the intricate tissue-and aetiologyspecific relationships between TP53 and RB1 pathways in tumorigenesis.

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Section: Ink4acontrasting

confidence: 42%

RB1 and TP53 pathways in radiation-induced sarcomas

et al. 2007

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“…Three reports pertained to the same study (22,42,43), and two (42, 43) described outcomes on a subset of patients included in the other study (22). We retained the publication with the larger sample size, but we also used information for 2-year survival from the subset publications because no such data were provided in the publication with the (20) were included in another study (11). We accepted both studies, but we excluded these two patients from the first study (20).…”

Section: Resultsmentioning

confidence: 99%

“…No grading information was available in four studies (15,17,18,22). The mean or median age of patients included in each study ranged from 13 to 67 years across the eligible studies; generally, the populations were young, with the exception of two studies (11,12). All analyzed osteosarcomas were treated with combination chemotherapy regimens (at least three or four drugs) including doxorubicin, cisplatin, methotrexate, ifosfamide, dactinomycin, bleomycin, or cyclophosphamide in various combinations.…”

Section: Resultsmentioning

confidence: 99%

“…Many studies failed to show any relationship between TP53 status (either protein expression or the presence of gene alterations) and response to chemotherapy or disease progression (9, 10, 12-14, 17, 18, 22, 24). However other investigations suggested associations with poor response to chemotherapy and decreased survival (15,16,19,21), whereas others were apparently inconclusive (11,20,23). Most studies had limited sample size.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Significance of TP53 Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma

Pakos

Kyzas

Ioannidis

2004

Clinical Cancer Research

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Purpose: Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma.Experimental Design: We conducted a meta-analysis of 16 studies (n ‫؍‬ 499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios.Results: The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86 -1.71), and the negative LR was 0.91 (95% confidence interval, 0.77-1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23-3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07-2.91).Conclusions: TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.

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“…26 Codon 12 mutations were detected thanks to a naturally occurring HpaII site (CCGG) that is lost when the mutation occurs. HpaII digests the 71-bp-amplified fragment into two fragments (41-and 30-bp), thus revealing the presence of the normal allele, while the mutant allele remains within the undigested 71-bp fragment.…”

Section: Differential Pcr For Mdm2mentioning

confidence: 99%

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

et al. 2004

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Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P ¼ 0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P ¼ 0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P ¼ 0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

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Molecular Analysis of p53, MDM2, and H-ras Genes in Osteosarcoma and Malignant Fibrous Histiocytoma of Bone in Patients Older than 40 Years

Cited by 43 publications

References 31 publications

RB1 and TP53 pathways in radiation-induced sarcomas

RB1 and TP53 pathways in radiation-induced sarcomas

Prognostic Significance of TP53 Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

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